SK280965B6 - Method for the preparation of 1,3-oxazolidin-5-carboxylic acid - Google Patents

Abstract

A method of preparing 1,3-oxazolidin-5-carboxylic acid of the general formula (I) by reacting an ether of general formula (XIX) and phenylisoserine derivative. In the general forumlas (I) and (XIX), Ar is a phenyl or an optionally substituted alpha- or beta-naphthyl group, R1 represents a benzoyl group or a group of the formula R2-O-CO-, Ph represents a phenyl group substituted with one or several alkoxy groups and R3 represents a C1-4alkyl group or a phenyl group. The acids of formula (I) are particularly useful in preparing taxol, Taxoter or analogs thereof which have remarkable antitumor and antileukemia properties.

Description

Technical field

The invention relates to a process for the preparation of 1,3-oxazolidine-5-carboxylic acid.

BACKGROUND OF THE INVENTION

The process for the preparation of 1,3-oxazolidine-5-carboxylic acid disclosed in WO-A-92-09589 describes the substitution at the 2-position of the prepared products and the reactions used to prepare this acid.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of 1,3-oxazolidine-5-carboxylic acid of general formula (I)

in which

Ar represents a phenyl or α- or β-naphthyl group, which is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom), alkyl group, alkenyl group, alkynyl group phenyl, phenylalkyl, alkoxy, alkylthio, phenyloxy, phenylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, benzylamino, alkoxycarbonylamino, alkoxycarbonylamino, a cyano group and a trifluoromethyl group, the alkyl groups and the alkyl portions of the other groups having 1 to 4 carbon atoms, the alkenyl and alkynyl groups having 3 to 8 carbon atoms,

R ¹ represents a benzoyl group or R ² -O-CO- group in which

R ² is

- a straight or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group having 4 to 6 carbon atoms, or a bicycloalkyl group having 7 to 11 carbon atoms, these groups are optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxy, C 1-4 alkoxy, dialkylamino in which each alkyl radical contains 1-4 carbon atoms, piperidino, morpholino, 1-piperazinyl, optionally piperazinyl substituted in the 4-position by C 1 -C 4 alkyl or phenylalkyl, wherein the C 1 -C 4 alkyl radical, C 3 -C 6 cycloalkyl, cycloalkenyl having 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkoxycarbonyl in which the alkyl radical contains 1 to 4 carbon atoms, or

a phenyl group optionally substituted by one or more substituents selected from the group consisting of alkyl group containing 1 to 4 carbon atoms or alkyloxy group containing 1 to 4 carbon atoms, wherein the cycloalkyl, cycloalkenyl or bicycloalkyl groups may optionally be substituted with one or more alkyl groups containing 1 to 4 carbon atoms, and

Ph represents a phenyl group substituted with one or more alkoxy groups containing 1 to 4 carbon atoms.

The acid of formula (I) according to the invention can be obtained by reaction of an ether of formula (XIX)

Ph-CH ₂ -OR ³ (XIX), wherein Ph is as defined above and R ³ is C 1-4 alkyl or aryl, with a phenylisoserine derivative of formula (XVI),

preferably in the form of 2R, 3S, working in an organic solvent selected from ethers, esters, ketones, nitriles, optionally halogenated aliphatic hydrocarbons and optionally halogenated aromatic hydrocarbons, in the presence of an oxidizing agent such as dichlorodicyanobenzoquinone, at a temperature between 0 ° C and the boiling point of the reaction mixture, followed by saponification of the thus obtained ester of formula (II) in a basic medium.

The process according to the invention makes it possible to obtain an acid of formula (I) which is substantially free of its epimer of formula (XX)

(XX> I in which Ar, R ¹ and Ph are as defined above).

It follows that this acid of formula (I) allows the preparation of the taxane derivatives of formula (XXI)

in which Ar and R ^{1 are} as defined above and R ⁴ represents a hydrogen atom or an acetyl group which is substantially free of the epimer at the 2 'position.

Taxane derivatives of formula (XXI) may be obtained by:

- condensation of an acid of formula (I) or a derivative thereof with baccatin III or 10-deacetylbaccatin III of formula (XXII)

SK 280965 Β6

wherein G ¹ is a hydroxyfunctional protecting group and G ² is an acetyl or hydroxyfunctional protecting group to form compounds of the general formula

in which Ar, R ¹ , Ph, G ¹ and G ^{2 are} as defined above,

- deprotection of the side chain and optionally hydroxyfunction protected by G ¹ and G ² to form compounds of the general formula

wherein Ar and R ^{1 are} as defined above, G ¹ represents a hydrogen atom or a hydroxyfunctional protecting group and G ² represents a hydrogen atom or an acetyl group or a hydroxyfunctional protecting group, and then

optionally replacing the protecting groups G ' ¹ and optionally G ^{2 of a} compound of formula (XXIV) with hydrogen atoms to form compounds of formula (XXI).

The esterification of the compound of formula (XXII) is carried out using an acid of formula (I), optionally in the form of an anhydride or in the form of a halide, or a mixed anhydride.

Preferably, an acid of formula (I) or activated derivatives thereof is used in which Ph represents a phenyl group optionally substituted by one or more electron-donor groups, in particular selected from the group consisting of C 1 -C 4 alkoxy groups.

The esterification using an acid of formula (I) may be carried out in the presence of a condensing agent such as carbodiimide such as dicyclohexylcarbodiimide or a reactive carbonate such as 2-dipyridyl carbonate and an activating agent such as aminopyridine such as 4-dimethylaminopyridine or 4-pyrrolidinopyrid working in an organic solvent selected from ethers such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether or dioxane, ketones such as methyl isobutyl ketone, esters such as ethyl acetate, isopropyl acetate or n-butyl acetate, nitriles such as acetonitrile, aliphatic hydrocarbons such as pentane, hexane or heptane, halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane, and aromatic hydrocarbons such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene or chlorobenzene at a temperature between -10 and 90 ° C. Said esterification is particularly preferably carried out by operating in an aromatic solvent at a temperature close to 20 ° C.

Said esterification can also be carried out using an acid of formula (I) in the form of an anhydride of formula (XXV)

wherein Ar, R ¹ and Ph are as defined above, in the presence of an activating agent such as aminopyridine, such as 4-dimethylaminopyridine, working in an organic solvent selected from the group consisting of ethers such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether or dioxane, ketones such as methyl isobutyl ketone, esters such as ethyl acetate, isopropyl acetate or n-butyl acetate, nitriles such as acetonitrile, aliphatic hydrocarbons such as pentane, hexane or heptane, halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloromethane , and aromatic hydrocarbons such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene or chlorobenzene, at a temperature between 0 and 90 ° C.

The esterification may also be carried out using an acid of formula (I) in the form of a halide or a mixed anhydride of formula (XXVI).

in which Ar, R ¹ and Ph are as defined above and X ¹ is a halogen atom or an acyloxy or aroyloxy group, optionally prepared in situ, in the presence of a base which is preferably a nitrogenous organic base such as a tertiary aliphatic amine such as triethylamine, pyridine, an aminopyridine, such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine, operating in an inert organic solvent selected from ethers such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether or dioxane, esters such as ethyl acetate, isopropyl acetate or n-butyl acetate, nitriles such as acetonitrile, aliphatic hydrocarbons such as pentane, hexane or heptane, halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane, and aromatic hydrocarbons such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene, or chlorobenzene, a temperature between 10 and 80 ° C, preferably at a temperature near 20 ° C.

Preferably, an activated derivative of general formula (XXVI) is used in which X ¹ represents a halogen atom or an acyloxy group containing 1 to 5 carbon atoms, or an aroyloxy group in which the aryl radical is a phenyl group optionally substituted by 1 to 5 identical or different substituents selected from including halogen atoms (chlorine atom, bromine atom), nitro, methyl and methoxy.

The side chain deprotection can be carried out in the presence of a mineral acid (hydrochloric acid, sulfuric acid) or an organic acid (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid) which is used alone or in a mixture working in an organic solvent selected from the group consisting of alcohols (methanol, ethanol, propanol, isopropanol), ethers (tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether), esters (ethyl acetate, isopropyl acetate, n-butyl acetate), aliphatic hydrocarbons (pentane, hexane, heptane), halogenated aliphatic hydrocarbons (dichloromethane, 1,2-dichloroethane), aromatic hydrocarbons (benzene, toluene, xylenes) and nitriles (acetonitrile) at a temperature between 10 and 60 ° C, preferably between 15 and 30 ° C. The mineral or organic acid may be used in a catalytic amount or in a stoichiometric amount or in excess.

The deprotection can also be carried out under oxidizing conditions using, for example, ammonium nitrate and cerium nitrate in a mixture of acetonitrile and water, or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a mixture of dichloromethane and water.

Deprotection can also be carried out under reducing conditions, for example by hydrogenolysis in the presence of a catalyst.

Protecting groups G ¹ and G ² are preferably 2,2,2-trichloroethoxycarbonyl, 2- (2-trichloromethylpropoxy) carbonyl, benzyl, 4-alkoxybenzyl or 2,4-dialkoxybenzyl, in which the alkoxy groups contain 1 to 4 carbon atoms , a trialkylsilyl group, a dialkylarylsilyl group, an alkyldiarylsilyl group or a triarylsilyl group wherein the alkyl radicals contain 1 to 4 carbon atoms and the aryl radicals are preferably phenyl groups.

The replacement of the protecting groups G ¹ and optionally G ² , which are silylated groups, with hydrogen atoms can be carried out simultaneously with the side chain dcprotection.

The replacement of the protecting groups G ¹ and optionally G ³ , which are 2,2,2-trichloroethoxycarbonyl or 2- (2-trichloromethylpropoxy) carbonyl, is carried out with zinc, optionally in combination with copper, in the presence of acetic acid at a temperature between 20 and 70 ° C or by using a mineral acid or an organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or in an aliphatic ester such as ethyl acetate, isopropyl acetate or n-butyl acetate in the presence of zinc, in combination with copper.

The acids of formula (I) are particularly suitable for the preparation of taxane derivatives of formula (XXI) wherein R ⁴ is acetyl, R ¹ is benzoyl and Ar is phenyl (taxol) or also wherein R ⁴ is hydrogen, R ¹ represents a tert-butoxycarbonyl group and Ar represents a phenyl group (Taxoter).

In the following, the invention will be explained in more detail by way of examples of a specific embodiment thereof, these examples being illustrative only and not in any way limiting the scope of the invention, which is clearly defined by the definition of the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Into a 10 cm ³ flask equipped with a magnetic stirrer, distillation system and a solid reagent addition hopper was successively introduced 104 mg (0.35 mmol) of (2R, 3S) -methyl-3-tert-butoxycarbonylamino-3-phenyl- 2-hydroxypropionate, 243 mg (1.6 mmol) of p-methoxyphenylmethyl methyl ether, 5 cm ^{3 of} acetonitrile which was freshly distilled over calcium hydride, and several grains of molecular sieve 4A. The reaction mixture was then heated to reflux and 217 mg (0.96 mmol) of dichlorodicyano benzoquinone were added in one portion to the heated mixture using the above hopper to add solid reactants. The reaction mixture is then heated to reflux with stirring while removing the methanol formed by distillation. The reaction mixture was then diluted with anhydrous dichloromethane and then filtered through celite. The celite was washed four times with dichloromethane. The combined organic phases are washed three times with aqueous sodium bicarbonate (5% w / v), once with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Filtration and removal of the solvents under reduced pressure yielded 331 mg of an oily residue which was purified by silica gel column chromatography (silica gel impregnated with 2.5% (v / v) triethylamine), eluting with a mixture of hexane and ethyl acetate (95% by volume). 5. This gives 136 mg of a melting product which is crystallized from a mixture of dichloromethane and hexane. 110 mg (0.27 mmol) of (2R, 4S, 5R) -3-tert-butoxycarbonyl-4-phenyl-2- (4-methoxyphenyl) -5-methoxycarbonyl-1,3-oxazolidine are thus obtained in a yield of 77%. having the following characteristics: melting point: 104-105 ° C (dichloromethane-hexane), optical rotation: [alpha] _D ²⁵ = + 58.7 ⁰ (c = 0.85, CHCl ₃ ), infrared (film) :

characteristic absorption bands at 2970, 2950, 2920, 2840, 1765, 1740, 1710, 1620, 1590, 1520, 1395, 1385, 1375, 1255, 1175, 1140, 1030, 930, and 830 cm ^-1 , ¹ H-nuclear magnetic resonance spectrum (200 MHz, CDC1 _3, chemical shifts in ppm, coupling constants J in Hz)

1.07 (s, 9H); 3.59 (s, 3H);

3.81 (s, 3H), 4.57 (d, J = 4.1, 1H),

5.41 (broad s, 1H),

6.37 (broad s, 1H),

6.91 (d, J = 8.8, 2H),

7.28-7.40 (m, 7H), ¹³ C-nuclear magnetic resonance spectrum (50.3 MHz,

CDC1 ₃ ):

27.81 _(CH3);

55.27 _(CH3);

80.64 (C),

91.95 (CH),

126.34 (CH),

128.32 (CH),

130.85 (C),

151.69 (C),

170.20 (C),

52.42 _(CH3);

63.30 (CH),

83.00 (CH)

113.63 (CH),

127.92 (CII),

128.72 (CH),

140.74 (C),

160.10 (C), mass spectrum (ic, NH ₃ + isobutane):

414 (MH ⁺ ), 375, 358, 314, 250, 206, elemental analysis: (C ₂₃ H ₂₇ NO ₆ )

C (%) H (%) N (%) calculated 66.81 6.58 3.39 found 66.85 6.56 3.45

A 15 cm @ ³ flask equipped with a magnetic stirrer was charged with 42 mg (0.102 mmol) of the pure product obtained and 4 cm @ ^{3 of} methanol under argon. Then 2 cm ^{3 of} distilled water and 41.4 mg (0.3 mmol) of solid potassium carbonate are added. The reaction mixture is allowed to react at a temperature close to 20 ° C for 15 hours. When the reaction is complete, methanol is removed under reduced pressure, and then 10 cm ^{3 of} water are added to the residue. The alkaline aqueous phase is extracted three times with 10 cm @ ^{3 of} dichloromethane. This aqueous phase is then

It is cooled to 0 ° C and then acidified with 1N hydrochloric acid solution with vigorous stirring and in the presence of 20 cm ^{3 of} dichloromethane until a pH of 1-2 is reached. The acidic aqueous phase is extracted five times with 15 cm ^{3 of} dichloromethane. The combined organic phases are washed three times with 5 cm @ ^{3 of} water, once with cm @ ^{3 of a} saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After filtration and removal of the solvents under reduced pressure, (2R, 4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl (40 mg, 0.1 mmol) was obtained in 98% yield. -1,3-oxazolidine-5-carboxylic acid having the following characteristics:

Melting point: 140-141 ° C, Infrared (film):

characteristic absorption bands at 3700-2300, 2985, 2925, 1770, 1710, 1615, 1595, 1520, 1410, 1370, 1250, 1175, 1090, 1035, 920, 830, 730 and 700 cm ^-1 , ¹ H-nuclear magnetic resonance spectrum (200 MHz, CDC1 _3, chemical shifts in ppm, coupling constants J in Hz):

1.06 (s, 9H); 3.81 (s, 3H);

4.61 (d, J = 4.2, 1H),

5.40 (d deform, J = 4.7, 1H),

5.54 (very broad, 1H),

6.38 (s, 1H), 6.89-6.95 (m, 2H),

7.26-7.42 (m, 7 H), ¹³ C-nucleating NMR (75.5 MHz, CDC1 _3, chemical shift in ppm):

27.29 _(CH3);

63.67 (CH),

82.66 (CH),

113.94 (CH),

128.08 (CH),

128.82 (CH),

140.42 C

160.43 C

55.28 _(CH3), 81.04 (C),

92.39 (CH),

126.33 (CH),

128.37 (CH),

130.51 (C),

151.71 (C),

172.67 (C), mass spectrum (IC, NH ₃ + isobutane):

417 (MH ⁺ + NH 3), 400 (MH ⁺ ), 361, 356, 344, 317, 300, 264, 256, 236, 213, 199, 180, 154, 137, 124, 110, elemental analysis:

(C ₂₂ H ₂₅ NO ₆ )

C (%) H (%) N (%) calculated 66.14 6.31 3.51 found 66.01 6.35 3.56

Claims (4)

Process for the preparation of 1,3-oxazolidine-5-carboxylic acid of general formula (I) A * _to COOH R, alkynyl, phenyl, phenylalkyl, alkoxy, alkylthio, phenyloxy, phenylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, benzylamino, alkoxycarbonyl, alkoxycarbonylamino, carboxy, a carbamoyl group, a dialkylcarbamoyl group, a cyano group and a trifluoromethyl group, the alkyl groups and the alkyl portions of the other groups having 1 to 4 carbon atoms, the alkenyl and alkynyl groups having 3 to 8 carbon atoms, R ¹ represents a benzoyl group or R ² -O-CO- group in which R ² is - a straight or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group having 4 to 6 carbon atoms or a bicycloalkyl group having 7 to 11 carbon atoms, these groups being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxy, C1-C4 alkoxy, dialkylamino in which each alkyl radical contains 1 to 4 carbon atoms, piperidino, morpholino, 1-piperazinyl, optionally substituted in the 4-position by C 1 -C 4 alkyl or phenylalkyl, in which the alkyl radical contains 1 to 4 carbon atoms, C 3 -C 6 cycloalkyl, cycloalkenyl another having 4 to 6 carbon atoms, a phenyl group, a cyano group, a carboxy group or an alkoxycarbonyl group in which the alkyl radical contains 1 to 4 carbon atoms, or a phenyl group optionally substituted by one or more substituents selected from the group consisting of C 1-4 alkyl or C 1-4 alkyloxy, wherein the cycloalkyl, cycloalkenyl or bicycloalkyl groups may be optionally substituted by one or more alkyl groups 1-4 carbon atoms, and Ph represents a phenyl group substituted by one or more alkoxy groups containing 1 to 4 carbon atoms, characterized in that the ether of formula (XIX) Ph-CH ₂ -OR ³ (XIX), wherein Ph is as defined above and R ³ is C 1-4 alkyl or phenyl, is reacted with a phenylisoserine derivative of formula Ar COOR R ^{1 -NHOH} wherein Ar and R ¹ are as defined above and R is C 1 -C 4 alkyl optionally substituted by phenyl, the reaction being carried out in an organic solvent in the presence of an oxidizing agent at a temperature between 0 ° C and boiling point of the reaction mixture and then obtaining an ester of the general formula wherein Ar represents a phenyl or α- or β-naphthyl group, which is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom), alkyl group, alkenyl in which Ar R ¹ , R 1 and Ph have the above-mentioned meanings, saponified in a basic environment by known methods. 2. A process according to claim 1, wherein a solvent selected from the group consisting of ethers, esters, ketones, nitriles, optionally halogenated aliphatic hydrocarbons and optionally halogenated aromatic hydrocarbons is used. The process according to claim 2, wherein an anhydrous organic solvent is used. 4. The process of claim 1 wherein the oxidizing agent is dichlorodicyanobenzoquinone.